ITCH_MOUSE
ID ITCH_MOUSE Reviewed; 864 AA.
AC Q8C863; O54971;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2003, sequence version 2.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=E3 ubiquitin-protein ligase Itchy;
DE EC=2.3.2.26 {ECO:0000269|PubMed:15358865, ECO:0000269|PubMed:16446428, ECO:0000269|PubMed:17592138, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:25632008};
DE AltName: Full=HECT-type E3 ubiquitin transferase Itchy homolog;
GN Name=Itch;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DISEASE, AND TISSUE SPECIFICITY.
RC STRAIN=C3H/HeJ; TISSUE=Kidney;
RX PubMed=9462742; DOI=10.1038/ng0298-143;
RA Perry W.L., Hustad C.M., Swing D.A., O'Sullivan T.N., Jenkins N.A.,
RA Copeland N.G.;
RT "The itchy locus encodes a novel ubiquitin protein ligase that is disrupted
RT in a18H mice.";
RL Nat. Genet. 18:143-146(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J; TISSUE=Head;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH NDFIP1.
RX PubMed=11748237; DOI=10.1074/jbc.m110443200;
RA Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S.;
RT "N4WBP5, a potential target for ubiquitination by the Nedd4 family of
RT proteins, is a novel Golgi-associated protein.";
RL J. Biol. Chem. 277:9307-9317(2002).
RN [5]
RP FUNCTION, AND INTERACTION WITH JUN AND JUNB.
RX PubMed=11828324; DOI=10.1038/ni763;
RA Fang D., Elly C., Gao B., Fang N., Altman Y., Joazeiro C., Hunter T.,
RA Copeland N.G., Jenkins N.A., Liu Y.C.;
RT "Dysregulation of T lymphocyte function in itchy mice: a role for Itch in
RT TH2 differentiation.";
RL Nat. Immunol. 3:281-287(2002).
RN [6]
RP INTERACTION WITH NOTCH1, AND MUTAGENESIS OF CYS-832.
RX PubMed=10940313; DOI=10.1074/jbc.m007300200;
RA Qiu L., Joazeiro C., Fang N., Wang H.-Y., Elly C., Altman Y., Fang D.,
RA Hunter T., Liu Y.-C.;
RT "Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin
RT ligase.";
RL J. Biol. Chem. 275:35734-35737(2000).
RN [7]
RP INTERACTION WITH OCNL.
RX PubMed=11782481; DOI=10.1074/jbc.m111384200;
RA Traweger A., Fang D., Liu Y.-C., Stelzhammer W., Krizbai I.A., Fresser F.,
RA Bauer H.-C., Bauer H.;
RT "The tight junction-specific protein occludin is a functional target of the
RT E3 ubiquitin-protein ligase itch.";
RL J. Biol. Chem. 277:10201-10208(2002).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AUTOUBIQUITINATION, AND
RP PHOSPHORYLATION.
RX PubMed=15358865; DOI=10.1126/science.1099414;
RA Gao M., Labuda T., Xia Y., Gallagher E., Fang D., Liu Y.C., Karin M.;
RT "Jun turnover is controlled through JNK-dependent phosphorylation of the E3
RT ligase Itch.";
RL Science 306:271-275(2004).
RN [9]
RP INTERACTION WITH NDFIP1.
RX PubMed=17137798; DOI=10.1016/j.immuni.2006.10.012;
RA Oliver P.M., Cao X., Worthen G.S., Shi P., Briones N., MacLeod M.,
RA White J., Kirby P., Kappler J., Marrack P., Yang B.;
RT "Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T
RT cell activation and T helper 2 cell-mediated inflammation.";
RL Immunity 25:929-940(2006).
RN [10]
RP CATALYTIC ACTIVITY, PATHWAY, PHOSPHORYLATION AT SER-199; THR-222 AND
RP SER-232, INTERACTION WITH MAPK8, AUTOUBIQUITINATION, SUBUNIT, AND
RP MUTAGENESIS OF SER-199; THR-222; SER-232 AND 535-ARG--VAL-540.
RX PubMed=16446428; DOI=10.1073/pnas.0510664103;
RA Gallagher E., Gao M., Liu Y.C., Karin M.;
RT "Activation of the E3 ubiquitin ligase Itch through a phosphorylation-
RT induced conformational change.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:1717-1722(2006).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, AND INTERACTION
RP WITH N4BP1.
RX PubMed=17592138; DOI=10.1073/pnas.0701773104;
RA Oberst A., Malatesta M., Aqeilan R.I., Rossi M., Salomoni P., Murillas R.,
RA Sharma P., Kuehn M.R., Oren M., Croce C.M., Bernassola F., Melino G.;
RT "The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3
RT ligase Itch.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:11280-11285(2007).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND UBIQUITINATION OF NOTCH1.
RX PubMed=18628966; DOI=10.1371/journal.pone.0002735;
RA Chastagner P., Israel A., Brou C.;
RT "AIP4/Itch regulates Notch receptor degradation in the absence of ligand.";
RL PLoS ONE 3:E2735-E2735(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Heart, Kidney, Lung, Pancreas, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH P15 BID, AND
RP UBIQUITINATION OF P15 BID.
RX PubMed=20392206; DOI=10.1111/j.1742-4658.2010.07562.x;
RA Azakir B.A., Desrochers G., Angers A.;
RT "The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal
RT growth factor by promoting the ubiquitylation and degradation of the
RT truncated C-terminal portion of Bid.";
RL FEBS J. 277:1319-1330(2010).
RN [15]
RP INTERACTION WITH PI4K2A, AND TISSUE SPECIFICITY.
RX PubMed=23146885; DOI=10.1038/embor.2012.164;
RA Mossinger J., Wieffer M., Krause E., Freund C., Gerth F., Krauss M.,
RA Haucke V.;
RT "Phosphatidylinositol 4-kinase IIalpha function at endosomes is regulated
RT by the ubiquitin ligase Itch.";
RL EMBO Rep. 13:1087-1094(2012).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, INTERACTION
RP WITH NDFIP1 AND UBE2L3, AND IDENTIFICATION IN COMPLEX WITH NDFIP1 AND
RP MAP3K7.
RX PubMed=25632008; DOI=10.4049/jimmunol.1402742;
RA Kathania M., Zeng M., Yadav V.N., Moghaddam S.J., Yang B., Venuprasad K.;
RT "Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7.";
RL J. Immunol. 194:2160-2167(2015).
RN [17]
RP INTERACTION WITH LDLRAD3.
RX PubMed=26854353; DOI=10.1021/acs.biochem.5b01218;
RA Noyes N.C., Hampton B., Migliorini M., Strickland D.K.;
RT "Regulation of Itch and Nedd4 E3 Ligase Activity and Degradation by
RT LRAD3.";
RL Biochemistry 55:1204-1213(2016).
RN [18]
RP STRUCTURE BY NMR OF 399-432 OF WILD TYPE AND IN VITRO WW3-PHOSPHORYLATED
RP FORMS.
RX PubMed=15971201; DOI=10.1002/prot.20466;
RA Shaw A.Z., Martin-Malpartida P., Morales B., Yraola F., Royo M.,
RA Macias M.J.;
RT "Phosphorylation of either Ser16 or Thr30 does not disrupt the structure of
RT the Itch E3 ubiquitin ligase third WW domain.";
RL Proteins 60:558-560(2005).
RN [19]
RP STRUCTURE BY NMR OF 399-432 OF WILD TYPE AND IN VITRO PHOSPHORYLATED FORMS
RP IN COMPLEX WITH PPXY MOTIFS OF EPSTEIN-BARR VIRUS LMP2A.
RX PubMed=17437719; DOI=10.1016/j.str.2007.03.005;
RA Morales B., Ramirez-Espain X., Shaw A.Z., Martin-Malpartida P., Yraola F.,
RA Sanchez-Tillo E., Farrera C., Celada A., Royo M., Macias M.J.;
RT "NMR structural studies of the ItchWW3 domain reveal that phosphorylation
RT at T30 inhibits the interaction with PPxY-containing ligands.";
RL Structure 15:473-483(2007).
CC -!- FUNCTION: Acts as an E3 ubiquitin-protein ligase which accepts
CC ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a
CC thioester and then directly transfers the ubiquitin to targeted
CC substrates (PubMed:15358865, PubMed:16446428, PubMed:17592138,
CC PubMed:18628966, PubMed:20392206, PubMed:25632008). It catalyzes 'Lys-
CC 29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (By
CC similarity). Involved in the control of inflammatory signaling pathways
CC (By similarity). Is an essential component of a ubiquitin-editing
CC protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that
CC ensures the transient nature of inflammatory signaling pathways (By
CC similarity). Promotes the association of the complex after TNF
CC stimulation (By similarity). Once the complex is formed, TNFAIP3
CC deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes
CC the formation of 'Lys-48'-polyubiquitin chains (By similarity). This
CC leads to RIPK1 proteasomal degradation and consequently termination of
CC the TNF- or LPS-mediated activation of NFKB1 (By similarity).
CC Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-
CC dependent signal transduction pathways (By similarity). Regulates the
CC transcriptional activity of several transcription factors involved in
CC immune response (PubMed:15358865, PubMed:11828324). Ubiquitinates NFE2
CC by 'Lys-63' linkages and is implicated in the control of the
CC development of hematopoietic lineages (By similarity). Mediates JUN
CC ubiquitination and degradation (PubMed:15358865). Mediates JUNB
CC ubiquitination and degradation (PubMed:11828324, PubMed:15358865).
CC Critical regulator of type 2 helper T (Th2) cell cytokine production by
CC inducing JUNB ubiquitination and degradation (PubMed:11828324).
CC Involved in the negative regulation of MAVS-dependent cellular
CC antiviral responses (By similarity). Ubiquitinates MAVS through 'Lys-
CC 48'-linked conjugation resulting in MAVS proteasomal degradation (By
CC similarity). Following ligand stimulation, regulates sorting of Wnt
CC receptor FZD4 to the degradative endocytic pathway probably by
CC modulating PI42KA activity (By similarity). Ubiquitinates PI4K2A and
CC negatively regulates its catalytic activity (By similarity).
CC Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4
CC to the degradative endocytic pathway following ligand stimulation by
CC ubiquitinating endosomal sorting complex required for transport ESCRT-0
CC components HGS and STAM (By similarity). Targets DTX1 for lysosomal
CC degradation and controls NOTCH1 degradation, in the absence of ligand,
CC through 'Lys-29'-linked polyubiquitination (PubMed:18628966).
CC Ubiquitinates SNX9 (By similarity). Ubiquitinates MAP3K7 through 'Lys-
CC 48'-linked conjugation (PubMed:25632008). Involved in the regulation of
CC apoptosis and reactive oxygen species levels through the ubiquitination
CC and proteasomal degradation of TXNIP (By similarity). Mediates the
CC antiapoptotic activity of epidermal growth factor through the
CC ubiquitination and proteasomal degradation of p15 BID
CC (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is
CC enhanced in the presence of NDFIP1 (By similarity).
CC {ECO:0000250|UniProtKB:Q96J02, ECO:0000269|PubMed:11828324,
CC ECO:0000269|PubMed:15358865, ECO:0000269|PubMed:16446428,
CC ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:20392206,
CC ECO:0000269|PubMed:25632008}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.26; Evidence={ECO:0000269|PubMed:15358865,
CC ECO:0000269|PubMed:16446428, ECO:0000269|PubMed:17592138,
CC ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:20392206,
CC ECO:0000269|PubMed:25632008};
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding
CC (PubMed:25632008). Activated by PI4K2A-binding (By similarity).
CC Inhibited by DTX3L-binding (By similarity). Inhibited by N4BP1 binding
CC (PubMed:17592138). {ECO:0000250|UniProtKB:Q96J02,
CC ECO:0000269|PubMed:17592138, ECO:0000269|PubMed:25632008}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:15358865, ECO:0000269|PubMed:16446428,
CC ECO:0000269|PubMed:17592138, ECO:0000269|PubMed:18628966,
CC ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:25632008}.
CC -!- SUBUNIT: Monomer. Interacts (via WW domains) with OCNL
CC (PubMed:11782481). Interacts (via WW domains) with NOTCH1
CC (PubMed:10940313, PubMed:18628966). Interacts (via WW domains) JUN
CC (PubMed:11828324). Interacts with JUNB; the interaction promotes ITCH-
CC mediated ubiquitination and degradation of JUNB (PubMed:11828324).
CC Interacts with FYN; the interaction phosphorylates ITCH on Tyr-381
CC decreasing binding of JUNB (By similarity). Interacts (via WW domain 2)
CC with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase
CC activity (PubMed:17592138). Interacts with NDFIP1 and NDFIP2; the
CC interaction with NDFIP proteins activates the E3 ubiquitin-protein
CC ligase and may induce its recruitment to exosomes (PubMed:11748237,
CC PubMed:17137798, PubMed:25632008). Interacts with ARHGEF7 (By
CC similarity). Interacts with RNF11 (By similarity). Interacts (via the
CC WW 1 domain) with NFE2 (via the PXY motif 1); the interaction promotes
CC 'Lys-63'-linked ubiquitination of NFE2, retains it in the cytoplasm and
CC prevents its transactivation activity (By similarity). Interacts (via
CC WW domains) with CXCR4 (via C-terminus); the interaction depends on
CC CXCR4 phosphorylation (By similarity). Found in a complex with E3
CC ligase DTX3L and ESCRT-0 components HGS and STAM (By similarity).
CC Interacts with DTX3L (via C-terminus); the interaction is increased
CC upon CXCL12 stimulation and inhibits ITCH catalytic activity (the
CC interaction is direct) (By similarity). Interacts with HGS (By
CC similarity). Interacts (via WW domains) with PCBP2 within a complex
CC containing ITCH, MAVS and PCBP2 (By similarity). Interacts (via WW
CC domains) with TXNIP (via C-terminus) (By similarity). Interacts with
CC p15 BID (PubMed:20392206). Interacts with ERBB4 (By
CC similarity).Interacts with DTX1 (By similarity). Interacts with SPART
CC (By similarity). Interacts with SNX9 and SNX18 (By similarity).
CC Interacts (via its WW domains) with ATN1 (By similarity). Interacts
CC (via WW domains) with SGK3 (By similarity). Interacts with CBLC (By
CC similarity). Interacts with OTUD7B (By similarity). Interacts (via WW
CC domain 1,2 and 3) with PI4K2A; the interaction inhibits PI4K2A
CC catalytic activity and promotes ITCH catalytic activity
CC (PubMed:23146885). Interacts with ARRDC4 (By similarity). Part of a
CC complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts
CC with UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008).
CC Interacts with MAPK8/JNK1 (PubMed:16446428). Interacts (via WW domains)
CC with ARRDC1 (via PPxY motifs); the interaction is direct and
CC participates in the recruitment of the ubiquitin-protein ligase ITCH to
CC the NOTCH1 receptor (By similarity). Interacts (via WW domains) with
CC ARRDC2 (By similarity). Interacts (via WW domains) with ARRDC3 (By
CC similarity). Interacts directly with LDLRAD3; this interaction promotes
CC ITCH auto-ubiquitination leading to its degradation (PubMed:26854353).
CC {ECO:0000250|UniProtKB:Q96J02, ECO:0000269|PubMed:10940313,
CC ECO:0000269|PubMed:11748237, ECO:0000269|PubMed:11782481,
CC ECO:0000269|PubMed:11828324, ECO:0000269|PubMed:16446428,
CC ECO:0000269|PubMed:17137798, ECO:0000269|PubMed:17592138,
CC ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:23146885,
CC ECO:0000269|PubMed:25632008, ECO:0000269|PubMed:26854353}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Epstein-Barr virus LMP2A.
CC {ECO:0000269|PubMed:17437719}.
CC -!- INTERACTION:
CC Q8C863; Q80TQ2: Cyld; NbExp=2; IntAct=EBI-851782, EBI-943859;
CC Q8C863; O89091: Klf10; NbExp=4; IntAct=EBI-851782, EBI-10949150;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q96J02};
CC Peripheral membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic
CC side {ECO:0000250|UniProtKB:Q96J02}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q96J02}. Nucleus {ECO:0000250|UniProtKB:Q96J02}.
CC Early endosome membrane {ECO:0000250|UniProtKB:Q96J02}; Peripheral
CC membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:Q96J02}. Endosome membrane
CC {ECO:0000250|UniProtKB:Q96J02}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:Q96J02}. Note=May be recruited to exosomes by
CC NDFIP1. Localizes to plasma membrane upon CXCL12 stimulation where it
CC co-localizes with CXCL4. Localization to early endosomes is increased
CC upon CXCL12 stimulation where it co-localizes with DTX3L and CXCL4.
CC {ECO:0000250|UniProtKB:Q96J02}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8C863-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8C863-2; Sequence=VSP_008452, VSP_008453;
CC -!- TISSUE SPECIFICITY: Detected in uterus (at protein level)
CC (PubMed:23146885). Widely expressed (PubMed:9462742).
CC {ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:9462742}.
CC -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing
CC proteins. {ECO:0000250|UniProtKB:Q96J02}.
CC -!- PTM: On T-cell activation, phosphorylation by the JNK cascade on serine
CC and threonine residues surrounding the PRR domain accelerates the
CC ubiquitination and degradation of JUN and JUNB. The increased ITCH
CC catalytic activity due to phosphorylation by JNK1 may occur due to a
CC conformational change disrupting the interaction between the PRR/WW
CC motifs domain and the HECT domain and, thus exposing the HECT domain.
CC Phosphorylation by FYN reduces interaction with JUNB and negatively
CC controls JUN ubiquitination and degradation. Interacts directly with
CC LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to
CC its degradation (PubMed:26854353). {ECO:0000269|PubMed:15358865,
CC ECO:0000269|PubMed:16446428, ECO:0000269|PubMed:18628966,
CC ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:26854353}.
CC -!- PTM: Monoubiquitinated. Autopolyubiquitinated with 'Lys-63' linkages
CC which does not lead to protein degradation.
CC {ECO:0000250|UniProtKB:Q96J02}.
CC -!- DISEASE: Note=Defects in Itch are the cause of the itchy phenotype
CC which is an inflammatory and immunological condition characterized by
CC inflammation in the lung and stomach, hyperplasia in lymphoid and
CC hematopoietic cells and constant itching in the skin.
CC {ECO:0000269|PubMed:9462742}.
CC -!- MISCELLANEOUS: [Isoform 1]: Major form.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-11 is the initiator.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB99764.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF037454; AAB99764.1; ALT_INIT; mRNA.
DR EMBL; AK048303; BAC33298.1; -; mRNA.
DR EMBL; BC062934; AAH62934.1; -; mRNA.
DR CCDS; CCDS38293.1; -. [Q8C863-1]
DR RefSeq; NP_001230641.1; NM_001243712.1. [Q8C863-1]
DR RefSeq; NP_032421.2; NM_008395.3. [Q8C863-1]
DR PDB; 1YIU; NMR; -; A=399-432.
DR PDB; 2JO9; NMR; -; A=399-432.
DR PDB; 2JOC; NMR; -; A=399-432.
DR PDB; 5XMC; X-ray; 2.60 A; A=143-864.
DR PDBsum; 1YIU; -.
DR PDBsum; 2JO9; -.
DR PDBsum; 2JOC; -.
DR PDBsum; 5XMC; -.
DR AlphaFoldDB; Q8C863; -.
DR SMR; Q8C863; -.
DR BioGRID; 200813; 63.
DR DIP; DIP-29318N; -.
DR ELM; Q8C863; -.
DR IntAct; Q8C863; 13.
DR MINT; Q8C863; -.
DR STRING; 10090.ENSMUSP00000105307; -.
DR iPTMnet; Q8C863; -.
DR PhosphoSitePlus; Q8C863; -.
DR EPD; Q8C863; -.
DR jPOST; Q8C863; -.
DR MaxQB; Q8C863; -.
DR PaxDb; Q8C863; -.
DR PeptideAtlas; Q8C863; -.
DR PRIDE; Q8C863; -.
DR ProteomicsDB; 269105; -. [Q8C863-1]
DR ProteomicsDB; 269106; -. [Q8C863-2]
DR Antibodypedia; 10897; 338 antibodies from 42 providers.
DR DNASU; 16396; -.
DR Ensembl; ENSMUST00000029126; ENSMUSP00000029126; ENSMUSG00000027598. [Q8C863-1]
DR Ensembl; ENSMUST00000109685; ENSMUSP00000105307; ENSMUSG00000027598. [Q8C863-1]
DR GeneID; 16396; -.
DR KEGG; mmu:16396; -.
DR UCSC; uc008nkd.1; mouse. [Q8C863-2]
DR UCSC; uc008nke.2; mouse. [Q8C863-1]
DR CTD; 83737; -.
DR MGI; MGI:1202301; Itch.
DR VEuPathDB; HostDB:ENSMUSG00000027598; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000157014; -.
DR HOGENOM; CLU_002173_0_1_1; -.
DR InParanoid; Q8C863; -.
DR OMA; PFEDNQG; -.
DR OrthoDB; 167687at2759; -.
DR PhylomeDB; Q8C863; -.
DR TreeFam; TF323658; -.
DR BRENDA; 2.3.2.B8; 3474.
DR Reactome; R-MMU-1253288; Downregulation of ERBB4 signaling.
DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-MMU-2122948; Activated NOTCH1 Transmits Signal to the Nucleus.
DR Reactome; R-MMU-5610780; Degradation of GLI1 by the proteasome.
DR Reactome; R-MMU-5632684; Hedgehog 'on' state.
DR Reactome; R-MMU-8939236; RUNX1 regulates transcription of genes involved in differentiation of HSCs.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 16396; 4 hits in 72 CRISPR screens.
DR ChiTaRS; Itch; mouse.
DR EvolutionaryTrace; Q8C863; -.
DR PRO; PR:Q8C863; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q8C863; protein.
DR Bgee; ENSMUSG00000027598; Expressed in rostral migratory stream and 255 other tissues.
DR Genevisible; Q8C863; MM.
DR GO; GO:0005938; C:cell cortex; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005769; C:early endosome; ISO:MGI.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISA:MGI.
DR GO; GO:1990763; F:arrestin family protein binding; ISO:MGI.
DR GO; GO:0045236; F:CXCR chemokine receptor binding; ISO:MGI.
DR GO; GO:0016874; F:ligase activity; IMP:BHF-UCL.
DR GO; GO:0043021; F:ribonucleoprotein complex binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISA:MGI.
DR GO; GO:0044389; F:ubiquitin-like protein ligase binding; ISO:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IMP:MGI.
DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:2000562; P:negative regulation of CD4-positive, alpha-beta T cell proliferation; IMP:MGI.
DR GO; GO:0050687; P:negative regulation of defense response to virus; IMP:UniProtKB.
DR GO; GO:0046329; P:negative regulation of JNK cascade; IMP:BHF-UCL.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI.
DR GO; GO:2000646; P:positive regulation of receptor catabolic process; ISO:MGI.
DR GO; GO:0002669; P:positive regulation of T cell anergy; IMP:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISO:MGI.
DR GO; GO:0051865; P:protein autoubiquitination; ISO:MGI.
DR GO; GO:0030163; P:protein catabolic process; IMP:MGI.
DR GO; GO:0035519; P:protein K29-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IMP:BHF-UCL.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:MGI.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0090085; P:regulation of protein deubiquitination; IMP:BHF-UCL.
DR GO; GO:0002870; P:T cell anergy; IMP:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:MGI.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd00201; WW; 4.
DR Gene3D; 2.60.40.150; -; 1.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR024928; E3_ub_ligase_SMURF1.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR InterPro; IPR001202; WW_dom.
DR InterPro; IPR036020; WW_dom_sf.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 3.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 4.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 4.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 4.
DR PROSITE; PS50020; WW_DOMAIN_2; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Antiviral defense;
KW Apoptosis; Cell membrane; Cytoplasm; Endosome; Immunity; Innate immunity;
KW Membrane; Nucleus; Phosphoprotein; Reference proteome; Repeat; Transferase;
KW Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q96J02"
FT CHAIN 2..864
FT /note="E3 ubiquitin-protein ligase Itchy"
FT /id="PRO_0000120318"
FT DOMAIN 1..115
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 287..320
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 319..352
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 399..432
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 439..472
FT /note="WW 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 530..864
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 151..294
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 356..432
FT /note="Required for interaction with FYN"
FT /evidence="ECO:0000250"
FT REGION 535..544
FT /note="MAP kinase docking site"
FT COMPBIAS 164..178
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 191..206
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 211..227
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 228..283
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 832
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:Q96J02"
FT MOD_RES 199
FT /note="Phosphoserine; by MAPK8"
FT /evidence="ECO:0000269|PubMed:16446428"
FT MOD_RES 222
FT /note="Phosphothreonine; by MAPK8"
FT /evidence="ECO:0000269|PubMed:16446428"
FT MOD_RES 232
FT /note="Phosphoserine; by MAPK8"
FT /evidence="ECO:0000269|PubMed:16446428"
FT MOD_RES 346
FT /note="Phosphothreonine; by SGK3"
FT /evidence="ECO:0000250|UniProtKB:Q96J02"
FT MOD_RES 381
FT /note="Phosphotyrosine; by FYN"
FT /evidence="ECO:0000250|UniProtKB:Q96J02"
FT MOD_RES 411
FT /note="Phosphoserine; by SGK3"
FT /evidence="ECO:0000250|UniProtKB:Q96J02"
FT VAR_SEQ 742..759
FT /note="LLCGMQEIDLNDWQRHAI -> MNFYLLKHTSKYSFRYLF (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_008452"
FT VAR_SEQ 760..864
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_008453"
FT MUTAGEN 199
FT /note="S->A: No loss of MAPK8-mediated phosphorylation and
FT no effect on ligase activity. Almost complete inactivation
FT of ligase activity; when associated with A-232. Greatly
FT reduced MAPK8-mediated phosphorylation; when associated
FT with A-222 or A-232. Completely abolishes MAPK8-mediated
FT phosphorylation; when associated with A-222 and A-232."
FT /evidence="ECO:0000269|PubMed:16446428"
FT MUTAGEN 199
FT /note="S->D: More sensitive to in vitro proteolysis."
FT /evidence="ECO:0000269|PubMed:16446428"
FT MUTAGEN 222
FT /note="T->A: No loss of MAPK8-mediated phosphorylation.
FT Greatly reduced MAPK8-mediated phosphorylation; when
FT associated with A-199 or A-232. Completely abolishes MAPK8-
FT mediated phosphorylation; when associated with A-199 and A-
FT 232."
FT /evidence="ECO:0000269|PubMed:16446428"
FT MUTAGEN 222
FT /note="T->D: Inhibits in vitro interaction between ITCH
FT HECT domain and PRR/WW motifs. More sensitive to in vitro
FT proteolysis."
FT /evidence="ECO:0000269|PubMed:16446428"
FT MUTAGEN 232
FT /note="S->A: No loss of MAPK8-mediated phosphorylation and
FT no effect on ligase activity. Almost complete inactivation
FT of ligase activity; when associated with A-199. Greatly
FT reduced MAPK8-mediated phosphorylation; when associated
FT with A-199 or A-222. Completely abolishes MAPK8-mediated
FT phosphorylation; when associated with A-199 and A-222."
FT /evidence="ECO:0000269|PubMed:16446428"
FT MUTAGEN 232
FT /note="S->D: More sensitive to in vitro proteolysis."
FT /evidence="ECO:0000269|PubMed:16446428"
FT MUTAGEN 535..540
FT /note="RRRLWV->AAALWA: Abolishes interaction with MAPK8."
FT /evidence="ECO:0000269|PubMed:16446428"
FT MUTAGEN 535..537
FT /note="RRR->AAA: Almost complete loss of interaction with
FT MAPK8."
FT MUTAGEN 535..536
FT /note="RR->AA: Greatly decreased interaction with MAPK8 and
FT ligase activity."
FT MUTAGEN 832
FT /note="C->A: Loss of ubiquitin protein ligase activity."
FT /evidence="ECO:0000269|PubMed:10940313"
FT STRAND 293..297
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 303..307
FT /evidence="ECO:0007829|PDB:5XMC"
FT TURN 308..311
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 312..316
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 325..329
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 335..339
FT /evidence="ECO:0007829|PDB:5XMC"
FT TURN 340..342
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 345..348
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 352..370
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 372..375
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 399..401
FT /evidence="ECO:0007829|PDB:2JOC"
FT STRAND 407..409
FT /evidence="ECO:0007829|PDB:1YIU"
FT STRAND 411..413
FT /evidence="ECO:0007829|PDB:1YIU"
FT STRAND 415..419
FT /evidence="ECO:0007829|PDB:1YIU"
FT TURN 420..423
FT /evidence="ECO:0007829|PDB:1YIU"
FT STRAND 424..426
FT /evidence="ECO:0007829|PDB:1YIU"
FT HELIX 489..503
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 505..512
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 518..528
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 531..534
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 536..541
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 550..564
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 568..570
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 573..575
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 582..585
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 587..591
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 595..612
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 622..628
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 635..641
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 643..649
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 712..725
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 728..731
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 736..744
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 751..756
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 771..779
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 782..793
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 803..805
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 815..819
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 823..825
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 828..830
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 831..833
FT /evidence="ECO:0007829|PDB:5XMC"
FT STRAND 835..838
FT /evidence="ECO:0007829|PDB:5XMC"
FT HELIX 844..856
FT /evidence="ECO:0007829|PDB:5XMC"
SQ SEQUENCE 864 AA; 98994 MW; 905FDBE00A1EA7EA CRC64;
MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT
NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL DIYETLKSNN MKLEEVVMTL
QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT NGETSCSEST TQNDDGCRTR DDTRVSTNGS
EDPEVAASGE NKRANGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD
GSSTGSLPPT NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH
GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP TLESVRNYEQ
WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP LPPGWEKRTD SNGRVYFVNH
NTRITQWEDP RSQGQLNEKP LPEGWEMRFT VDGIPYFVDH NRRATTYIDP RTGKSALDNG
PQIAYVRDFK AKVQYFRFWC QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV
IFPGEEGLDY GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR
FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI WVKENNIEEC
GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR MVAEWRLSRG VEEQTQAFFE
GFNEILPQQY LQYFDAKELE VLLCGMQEID LNDWQRHAIY RHYTRTSKQI MWFWQFVKEI
DNEKRMRLLQ FVTGTCRLPV GGFADLMGSN GPQKFCIEKV GKENWLPRSH TCFNRLDLPP
YKSYEQLKEK LLFAIEETEG FGQE
